Combinations comprising epothilones and pharmaceutical uses thereof

ABSTRACT

The invention relates to a combination which comprises (a) a bisphosphonate, a platinum compound or a vasculostatic compound and (b) an epothilone derivative of formula (I), wherein A represents O or NRN, wherein RN is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use, in particular for the delay of progression or treatment of a proliferative disease, especially a solid tumor disease; a pharmaceutical composition, a commercial package or product comprising such a combination; the use of such a combination for the preparation of a medicament for the delay of progression or treatment of a proliferative disease and to a method of treatment of a warm-blooded animal.

[0001] The invention relates to a combination which comprises (a) abisphosphonate, a platinum compound or a vasculostatic compound and (b)an epothilone derivative of formula I and optionally at least onepharmaceutically acceptable carrier for simultaneous, separate orsequential use, in particular for the delay of progression or treatmentof a proliferative disease, especially a solid tumor disease; apharmaceutical composition comprising such a combination; the use ofsuch a combination for the preparation of a medicament for the delay ofprogression or treatment of a proliferative disease; a commercialpackage or product comprising such a combination as a combinedpreparation for simultaneous, separate or sequential use; and to amethod of treatment of a warm-blooded animal, especially a human.

[0002] Despite the widespread use of Taxol® and Taxotere® in thetreatment of many different tumor types, the impact of taxanes onpatient survival has been modest, and the overwhelming majority ofmetastatic tumors remain incurable. Taxane treatment is associated witha number of significant side-effects, such as peripheral neuropathy andstomatitis, and the effectiveness of taxanes can be severely limited byrapidly-developing drug resistance mechanisms, possibly involvingtubulin mutations or overexpression of phosphoglycoproteins thatfunction as drug efflux pumps. In view of these limitations as well asin view of the side-effects commonly observed with standard combinationtherapies, there is clearly a need for the identification of novelcombinations that exhibit an improved overall profile including abroader spectrum of anti-tumor activity, efficacy against multi-drugresistant tumors and higher safety and tolerability.

[0003] The therapeutic efficacy of bisphosphonates has been demonstratedin the treatment of Paget's disease of bone, tumor-inducedhypercalcaemia, bone metastasis and multiple myeloma (H. Fleisch inBisphosphonates in Bone Disease. From the Laboratory to the Patient.Eds: The Parthenon Publishing Group, New York/London, 1997, p. 68 to163).

[0004] Direct evidence of the role of the “Vascular Endothelial GrowthFactor” (VEGF) as a tumour angiogenesis factor in Vivo has been obtainedfrom studies in which VEGF expression or VEGF activity was inhibited.This was achieved with antibodies which inhibit VEGF activity, withdominant-negative VEGFR-2 mutants which inhibited signal transduction,or with the use of antisense-VEGF RNA techniques. Small moleculesinhibiting the VEGF tyrosine kinase are disclosed, e.g., in WO98/35958.One of these molecules is known as PTK787.

[0005] The microtubule-stabilizing effect of epothilones was firstdescribed by Bollag et al., Cancer Research 55, 1995, 2325-33. Asuitable treatment schedule of different types of tumors, especiallytumors which are refractory to the treatment by other chemotherapeutics,in particular TAXOL™, is described in WO 99/43320.

[0006] The present invention pertains to a combination, such as acombined preparation or a pharmaceutical composition, which comprises(a) a bisphosphonate, a platinum compound or a vasculostatic compoundand (b) an epothilone derivative of formula I

[0007] wherein A represents O or NR_(N), wherein R_(N) is hydrogen orlower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, inwhich the active ingredients (a) and (b) are present in each case infree form or in the form of a pharmaceutically acceptable salt andoptionally at least one pharmaceutically acceptable carrier; forsimultaneous, separate or sequential use.

[0008] Unless stated otherwise, in the present disclosure organicradicals and compounds designated “lower” contain not more than 7,preferably not more than 4, carbon atoms.

[0009] A compound of formula I wherein A represents O, R is hydrogen andZ is O is known as epothilone A; a compound of formula I wherein Arepresents O, R is methyl and Z is O is known as epothilone B; acompound of formula I wherein A represents O, R is hydrogen and Z is abond is known as epothilone C; a compound of formula I wherein Arepresents O, R is methyl and Z is a bond is known as epothilone D.

[0010] The term “a combined preparation”, as used herein definesespecially a “kit of parts” in the sense that the combination partners(a) and (b) as defined above can be dosed independently or by use ofdifferent fixed combinations with distinguished amounts of thecombination partners (a) and (b), i.e., simultaneously or at differenttime points. The parts of the kit of parts can then, e.g., beadministered simultaneously or chronologically staggered, that is atdifferent time points and with equal or different time intervals for anypart of the kit of parts. Very preferably, the time intervals are chosensuch that the effect on the treated disease in the combined use of theparts is larger than the effect which would be obtained by use of onlyany one of the combination partners (a) and (b). The ratio of the totalamounts of the combination partner (a) to the combination partner (b) tobe administered in the combined preparation can be varied, e.g. in orderto cope with the needs of a patient sub-population to be treated or theneeds of the single patient which different needs can be due to age,sex, body weight, etc. of the patients. Preferably, there is at leastone beneficial effect, e.g., a mutual enhancing of the effect of thecombination partners (a) and (b), in particular a synergism, e.g. a morethan additive effect, additional advantageous effects, less sideeffects, a combined therapeutical effect in a non-effective dosage ofone or both of the combination partners (a) and (b), and very preferablya strong synergism of the combination partners (a) and (b).

[0011] The term “solid tumor disease” especially means breast cancer,ovarian cancer, cancer of the colon and generally the GI tract includinggastric cancer, cervix cancer, lung cancer, e.g. small-cell lung cancerand non-small-cell lung cancer, pancreas cancer, renal cancer, glioma,melanoma, head and neck cancer, bladder cancer, hepatocellular cancer,prostate cancer and Kaposi's sarcoma. Preferably, the proliferativedisease to be treated with a combination comprising a platinum compoundis ovarian cancer, lung cancer, head or neck cancer, cervix cancer,prostate cancer, colon cancer, breast cancer, renal cancer, carcinoidtumors, gastric cancer or hepatocellular cancer. Preferably, theproliferative disease to be treated with a combination comprising abisphosphonate is breast cancer, ovarian cancer or lung cancer. Inanother preferred embodiment of the invention, the proliferative diseaseto be treated with a COMBINATION OF THE INVENTION comprising avasculostatic compound, in particular PTK787, is ovarian cancer, breastcancer, lung cancer, head or neck cancer, cervix cancer, prostate canceror colon cancer.

[0012] The term “proliferative disease” as used herein comprises thesolid tumor diseases as listed above and furthermore Paget's disease ofbone, tumor-induced hypercalcaemia, bone metastasis and multiplemyeloma.

[0013] The term “a disease associated with deregulated angiogenesis”relates especially to diseases caused by ocular neovascularisation,especially retinopathies, such as diabetic retinopathy or age-relatedmacula degeneration, psoriasis, haemangioblastoma, such as haemangioma,mesangial cell proliferative disorders, such as chronic or acute renaldiseases, e.g. diabetic nephropathy, malignant nephrosclerosis,thrombotic micro-angiopathy syndromes or transplant rejection, orespecially inflammatory renal disease, such as glomerulonephritis,especially mesangioproliferative glomerulonephritis, haemolytic-uraemicsyndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma,arterial restenosis, autoimmune diseases, acute inflammation, fibroticdisorders (e.g. hepatic cirrhosis), neurodegenerative disorders, andespecially proliferative diseases, especially those proliferativediseases comprising tumours expressing c-kit, KDR or fit-1.

[0014] The term “bisphosphonates” as used herein includes, but is notlimited to etridonic acid, clodronic acid, tiludronic acid, pamidronicacid, alendronic acid, ibandronic acid, risedronic acid and zoledronicacid. “Etridonic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark DIDRONEL™. “Clodronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONEFOS™. “Tiludronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark SKELID™. “Pamidronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark AREDIA™. “Alendronic acid” can be administered,e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX™.“Ibandronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark BONDRANAT™. “Risedronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ACTONEL™. “Zoledronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ZOMETA™.

[0015] The term “platinum compound” as used herein means carboplatin,cisplatin or oxaliplatin.

[0016] The term “carboplatin” as used herein relates to theantineoplastic agent cis-diamine (1,1-cyclobutane dicarboxylato)platinum(II), which is disclosed, e.g., in U.S. Pat. No. 4,140,707 or byR. C. Harrison et al. in Inorg. Chim. Acta 46, L15 (1980). This drug canbe administered e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT™ or PARAPLATIN™.

[0017] The term “oxaliplatin” as used herein relates to theantineoplastic agent also known as oxalatoplatinum, which is disclosed,e.g., in U.S. Pat. No. 5,716,988. This drug can be administered e.g., inthe form as described in the cited U.S. patent or in the form it ismarketed, e.g. under the trademark ELOXANTINE™ or 1-OHP™.

[0018] The term “cisplatin” as used herein relates to the antineoplasticagent also known as cis-diaminedichloroplatinum, which compound and itsuse as antineoplastic agent is disclosed, e.g., in DE 2,318,020.

[0019] The term “vasculostatic compounds” as used herein comprises, butis not restricted to, active ingredients which decrease the activity ofthe VEGF, metalloproteinase inhibitors and other compounds having avasculostatic effect.

[0020] The active ingredient, which decreases the activity of the VEGF,is especially selected from the group consisting of compounds whichinhibit the VEGF receptor tyrosine kinase, compounds which inhibit aVEGF receptor and compounds binding to VEGF. The active ingredient,which decreases the activity of the VEGF, is in particular one of thosecompounds, proteins and monoclonal antibodies, which are generically andspecifically disclosed in WO 98/35958 (describing compounds of formulaII), WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO01/55114, WO 01/58899 and EP 0 769 947, which are described by M.Prewett et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et alin Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770, December 1996,by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordentiet al in Toxicologic Pathology, Vol. 27, no. 1, pp 14-21, 1999, thosewhich are generically and specifically disclosed in WO 00/37502 and WO94/10202; and those which are described by M. S. O'Reilly et al, Cell79, 1994, 315-328 (Angiostatin™) and by M. S. O'Reilly et al, Cell 88,1997, 277-285 (Endostatin™), in each case in particular in the compoundclaims, the pharmaceutical preparations and the final products of theworking examples, the subject-matter of which is hereby incorporatedinto the present application by reference to this publications.Comprised are likewise the corresponding stereoisomers as well as thecorresponding crystal modifications, e.g. solvates and polymorphs, whichare disclosed therein. The compounds used as active ingredients in thecombinations disclosed herein can be prepared and administered asdescribed in the cited documents, respectively.

[0021] The term “PTK787” as used herein means a compound of formula II

[0022] wherein r, n and m are each 0, R₁ and R₂ together form a bridgeof subformula II*,

[0023] A, B, D and E are each CH, G is methylene, X is imino, Y is4-chlorophenyl, and the bonds characterized by a wavy line are doublebonds, disclosed, e.g., in Example 38 of WO98/35958. Preferably, suchcompound is employed in the form of its succinate salt. This drug or itssalt can be administered, e.g., in the form as disclosed in the citedPCT patent application.

[0024] “Metalloproteinase inhibitors” as defined herein are, e.g.,Marimastat (BB-2516), Prinomastat (AG3340), Bay 12-9566, BMS-275291,MMI270B and Metastat (NSC 683551).

[0025] The term “other compounds having a vasculostatic effect” asdefined herein relates in particular to the compounds EMD-121974,doxorubicin, paclitaxel, IM-862, Thalidomide®), Linomide®, PKC412,AGM-1470, Suramin and Pentosan polysulfate.

[0026] Epothilone derivatives of formula I wherein A represents O orNR_(N), wherein R_(N) is hydrogen or lower alkyl, R is hydrogen or loweralkyl and Z is O or a bond, and methods for the preparation of suchepothilone derivatives are in particular generically and specificallydisclosed in the patents and patent applications WO 93/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247 in each case in particular in the compound claims and the finalproducts of the working examples, the subject-matter of the finalproducts, the pharmaceutical preparations and the claims is herebyincorporated into the present application by reference to thispublications. Comprised are likewise the corresponding stereoisomers aswell as the corresponding crystal modifications, e.g. solvates andpolymorphs, which are disclosed therein. Epothilone derivatives offormula I, especially epothilone B, can be administered as part ofpharmaceutical compositions which are disclosed in WO 99/39694.

[0027] The transformation of epothilone B to the corresponding lactam isdisclosed in Scheme 21 (page 31, 32) and Example 3 of WO 99/02514 (pages48-50). The transformation of a compound of formula I which is differentfrom epothilone B into the corresponding lactam can be accomplishedanalogously. Corresponding epothilone derivatives of formula I whereinR_(N) is lower alkyl can be prepared by methods known in the art such asa reductive alkylation reaction starting from the epothilone derivativewherein R_(N) is hydrogen.

[0028] Furthermore, the structure of the active agents mentioned hereinby name may be taken from the actual edition of the standard compendium“The Merck Index” or from databases, e.g. Patents International (e.g.IMS World Publications). The corresponding content thereof is herebyincorporated by reference. Any person skilled in the art is fullyenabled, based on these references, to manufacture and test thepharmaceutical indications and properties in standard test models, bothin vitro and in vivo.

[0029] The compounds used as combination partners (a) and (b) disclosedherein can be prepared and administered as described in the citeddocuments, respectively.

[0030] It will be understood that references to the combination partners(a) and (b) are meant to also include the pharmaceutically acceptablesalts. If these combination partners (a) and (b) have, for example, atleast one basic center, they can form acid addition salts. Correspondingacid addition salts can also be formed having, if desired, anadditionally present basic center. The combination partners (a) and (b)having an acid group (for example COOH) can also form salts with bases.The combination partner (a) or (b) or a pharmaceutically acceptable saltthereof may also be used in form of a hydrate or include other solventsused for crystallization.

[0031] A combination which comprises (a) a bisphosphonate, a platinumcompound or a vasculostatic compound and (b) an epothilone derivative offormula I in which compound A represents O or NR_(N), wherein R_(N) ishydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or abond, in which the active ingredients are present in each case in freeform or in the form of a pharmaceutically acceptable salt and optionallyat least one pharmaceutically acceptable carrier, will be referred tohereinafter as a COMBINATION OF THE INVENTION.

[0032] The COMBINATIONS OF THE INVENTION inhibits the growth of solidtumors, but also liquid tumors. In one preferred embodiment of theinvention, the disease to be treated is prostate cancer, in particularhormone refractory prostate cancer with bone metastasis. Furthermore, aCOMBINATIONS OF THE INVENTION comprising a vasculostatic compound, inparticular PTK787, exhibit beneficial effects in the treatment ofdiseases associated with deregulated angiogenesis.

[0033] The nature of proliferative diseases like solid tumor diseases ismultifactorial. Under certain circumstances, drugs with differentmechanisms of action may be combined. However, just considering anycombination of drugs having different mode of action does notnecessarily lead to combinations with advantageous effects.

[0034] All the more surprising is the experimental finding that in vivothe administration of a COMBINATION OF THE INVENTION compared to amonotherapy applying only one of the pharmaceutically active ingredientsused in the COMBINATION OF THE INVENTION results not only in a morebeneficial, especially synergistic, anti-proliferative effect, e.g. withregard to the delay of progression of a proliferative disease or withregard to a change in tumor volume, and/or more beneficial, especiallysynergistic, effect of preventing skeletal-related events (SREs), butalso in further surprising beneficial effects, e.g. less side-effectsand a decreased mortality and morbidity. Furthermore, depending on thetumor type and the particular combination used a decrease of the tumorvolume can be obtained when using a COMBINATION OF THE INVENTION incases in which by monotherapy no decrease of the tumor volume can beachieved. The COMBINATIONS OF THE INVENTION are also suitable to preventthe metastatic spread of tumors and the growth or development ofmicrometastases. The COMBINATION OF THE INVENTION are in particularsuitable for the treatment of poor prognosis patients, i.e. inparticular such patients that did not respond to or relapse after anearlier treatment with a single drug or a combination different to aCOMBINATION OF THE INVENTION.

[0035] A further benefit is that lower doses of the active ingredientsof the COMBINATION OF THE INVENTION can be used, for example, that thedosages need not only often be smaller but are also applied lessfrequently, or can be used in order to diminish the incidence ofside-effects. This is in accordance with the desires and requirements ofthe patients to be treated.

[0036] It can be shown by established test models and in particularthose test models disclosed herein that a COMBINATION OF THE INVENTIONresults in the beneficial effects described herein-before. The personskilled in the pertinent art is fully enabled to select a relevant testmodel to prove such beneficial effects. The pharmacological activity ofa COMBINATION OF THE INVENTION may, for example, be demonstrated in aclinical study or in a test procedure as essentially describedhereinafter.

[0037] Suitable clinical studies are in particular randomized,double-blind, placebo-controlled, parallel studies. Such studies are, inparticular, suitable to compare the effects of a monotherapy using theactive ingredients and a therapy using a COMBINATION OF THE INVENTION,and to prove in particular the synergism of the active ingredients ofthe COMBINATIONS OF THE INVENTION. The beneficial effects onproliferative diseases, e.g. to prevent skeletal-related events (SREs)in prostate cancer patients with a history of metastatic bone disease,can be determined directly through the results of these studies or bychanges in the study design which are known as such to a person skilledin the art. SREs are defined as pathologic bone fracture events, spinalcord compression events, surgery to bone, radiation therapy to bone anda change of antineoplastic therapy to treat bone pain. Preferably, SREsare the primary endpoints in such studies. Furthermore, in such studiesthe effect on pain scores, analgesic use, performance status, Quality ofLife scores, bone mineral density, time to progression in bone andoverall progression can be evaluated.

[0038] In a suitable study design, patients are randomized in adouble-blind fashion to receive every three weeks either 2 mgzoledronate intravenously as a 5-minute infusion or 15-minute infusion,4 mg zoledronate intravenously as a 5-minute infusion or 15-minuteinfusion, or a placebo intravenously as a 5-minute infusion or 15-minuteinfusion, in addition to a compound of formula I, e.g. 6 cycles ofepothilone B wherein each cycle consists of between 2.5 mg/m² and 6mg/m² epothilone B administered as a 5 minute bolus once a week forthree weeks followed by 14 days of rest.

[0039] In another suitable study design, patients are randomized in adouble-blind fashion to receive every two weeks 45 mg oxaliplatin/m²body surface intravenously as a 2 to 6 hour infusion or a correspondingplacebo in addition to a compound of formula I, e.g. 6 cycles ofepothilone B wherein each cycle consists of 2.5 mg/m² epothilone Badministered as a 5 minute bolus once a week for three weeks followed by14 days of rest.

[0040] In a further suitable study design, patients are randomized in adouble-blind fashion to receive daily, e.g., 250 or 500 mg PTK787 or acorresponding placebo in addition to a compound of formula I, e.g. 6cycles of epothilone B wherein each cycle consists of 2.5 mg/m²epothilone B administered as a 5 minute bolus once a week for threeweeks followed by 14 days of rest.

[0041] In another study design, weekly doses of 0.5 mg/m², 1.0 mg/m²,1.5 mg/m², 2.0 mg/m² or 2.5 mg/m² of epothilone B are applied asintravenous infusion over 5 minutes and cisplatin is dosed per standardguidelines, i.e. in a weekly dose of 20-100 mg/m² of body surface area,e.g. 30 mg/m² weekly. The cisplatin injection is diluted prior toadministration and administered immediately after epothilone B as aone-hour intravenous infusion. One cycle of treatment consists of theadministration of both drugs for three weeks followed by one week ofrest.

[0042] It is one objective of this invention to provide a pharmaceuticalcomposition comprising a quantity, which is jointly therapeuticallyeffective against a proliferative disease comprising the COMBINATION OFTHE INVENTION. In this composition, the combination partners (a) and (b)can be administered together, one after the other or separately in onecombined unit dosage form or in two separate unit dosage forms. The unitdosage form may also be a fixed combination.

[0043] The pharmaceutical compositions according to the invention can beprepared in a manner known per se and are those suitable for enteral,such as oral or rectal, and parenteral administration to mammals(warm-blooded animals), including man, comprising a therapeuticallyeffective amount of at least one pharmacologically active combinationpartner alone or in combination with one or more pharmaceuticallyacceptable carries, especially suitable for enteral or parenteralapplication.

[0044] The novel pharmaceutical composition contain, for example, fromabout 10% to about 100%, preferably from about 20% to about 60%, of theactive ingredients. Pharmaceutical preparations for the combinationtherapy for enteral or parenteral administration are, for example, thosein unit dosage forms, such as sugar-coated tablets, tablets, capsules orsuppositories, and furthermore ampoules. If not indicated otherwise,these are prepared in a manner known per se, for example by means ofconventional mixing, granulating, sugar-coating, dissolving orlyophilizing processes. It will be appreciated that the unit content ofa combination partner contained in an individual dose of each dosageform need not in itself constitute an effective amount since thenecessary effective amount can be reached by administration of aplurality of dosage units.

[0045] In preparing the compositions for oral dosage form, any of theusual pharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents; or carriers such as starches, sugars, microcristallinecellulose, diluents, granulating agents, lubricants, binders,disintegrating agents and the like in the case of oral solidpreparations such as, for example, powders, capsules and tablets, withthe solid oral preparations being preferred over the liquidpreparations. Because of their ease of administration, tablets andcapsules represent the most advantageous oral dosage unit form in whichcase solid pharmaceutical carriers are obviously employed.

[0046] In particular, a therapeutically effective amount of each of thecombination partners of the COMBINATION OF THE INVENTION may beadministered simultaneously or sequentially and in any order, and thecomponents may be administered separately or as a fixed combination. Forexample, the method of delay of progression or treatment of aproliferative disease according to the invention may comprise (i)administration of the first combination partner in free orpharmaceutically acceptable salt form and (ii) adminstration of thesecond combination partner in free or pharmaceutically acceptable saltform, simultaneously or sequentially in any order, in jointlytherapeutically effective amounts, preferably in synergisticallyeffective amounts, e.g. in daily dosages corresponding to the amountsdescribed herein. The individual combination partners of the COMBINATIONOF THE INVENTION can be administered separately at different timesduring the course of therapy or concurrently in divided or singlecombination forms. Furthermore, the term administering also encompassesthe use of a pro-drug of a combination partner that convert in vivo tothe combination partner as such. The instant invention is therefore tobe understood as embracing all such regimes of simultaneous oralternating treatment and the term “administering” is to be interpretedaccordingly.

[0047] The effective dosage of each of the combination partners employedin the COMBINATION OF THE INVENTION may vary depending on the particularcompound or pharmaceutical composition employed, the mode ofadministration, the condition being treated, the severity of thecondition being treated. Thus, the dosage regimen the COMBINATION OF THEINVENTION is selected in accordance with a variety of factors includingthe route of administration and the renal and hepatic function of thepatient. A physician, clinician or veterinarian of ordinary skill canreadily determine and prescribe the effective amount of the singleactive ingredients required to prevent, counter or arrest the progressof the condition. Optimal precision in achieving concentration of theactive ingredients within the range that yields efficacy withouttoxicity requires a regimen based on the kinetics of the activeingredients' availability to target sites. This involves a considerationof the distribution, equilibrium, and elimination of the activeingredients.

[0048] If the the warm-blooded animal is a human, the dosage of acompound of formula I is preferably in the range of about 0.25 to 75,preferably 0.5 to 50, e.g. 2.5, mg/m² once weekly for two to four, e.g.three, weeks, followed by 6 to 8 days off in the case of an adultpatient.

[0049] Epothilone B is preferably administered in a dose which iscalculated according to the formula (III)

single dose (mg/m2)=(0.1 to y)×N  (III)

[0050] wherein N is the number of weeks between treatments and y is 6,wherein epothilone B is administered in more than one treatment cycleafter an interval of one week to six weeks after the precedingtreatment.

[0051] In one preferred embodiment of the invention, epothilone B isadministered weekly in a dose that is between about 0.1 to 6 mg/m²,preferably between 0.1 and 3 mg/m², e.g. 2.5 or 3.0 mg/m², for threeweeks after an interval of one to six weeks, especially an interval ofone week, after the preceding treatment. In another embodiment of theinvention said epothilone B is preferably administered to a human every18 to 24 days in a dose that is between about 0.3 and 12 mg/m².

[0052] Unless stated otherwise herein, the bisphosphonates describedherein can be administered in the following dosages:

[0053] Alendronic acid may be administered to a human in a dosage rangevarying from about 5 to 10 mg/day.

[0054] Clodronic acid may be administered to a human e.g. in a dosagerange varying from about 750 to 1500 mg/day.

[0055] Etridonic acid may be administered to a human in a dosage rangevarying from about 200 to 400 mg/day.

[0056] Ibandronic acid may be administered to a human in a dosage rangevarying from about 1 to 4 mg every three to four weeks.

[0057] Risedronic acid may be administered to a human in a dosage rangevarying from about 20 to 30 mg/day.

[0058] Pamidronic acid may be administered to a human in a dosage rangevarying from about 15 to 90 mg every three to four weeks.

[0059] Tiludronic acid may be administered to a human in a dosage rangevarying from about 200 to 400 mg/day.

[0060] Zoledronic acid may be administered to a human in a dosage rangevarying from about 2 to 10 mg, especilly 4 or 8 mg, as an intravenousinfusion every 3 weeks.

[0061] Carboplatin may be administered intravenously to a human in adosage range varying from about 100 to 400, e.g. 200, mg/m² body surfaceabout every four to six weeks.

[0062] Oxaliplatin may be administered intravenously to a human in adosage range varying from about 25 to 135, e.g. 45 or 85, mg/m² bodysurface about every two to three weeks.

[0063] Cisplatin may be administered to a human in a dosage rangevarying from about 25 to 100 mg/m² about every three weeks.

[0064] If the the warm-blooded animal is a human, the dosage of PTK787is preferably in the range of about 50 to 1500, more preferably about100 to 750, and most preferably 250 to 500, mg/day.

[0065] In a preferred embodiment of the invention, the COMBINATION OFTHE INVENTION comprises a bisphosphonate selected from etridonic acid,clodronic acid, tiludronic acid, pamidronic acid, alendronic acid,ibandronic acid, risedronic acid and, most preferably, zoledronic acid.

[0066] In another embodiment of the invention, the COMBINATION OF THEINVENTION comprises cisplatin, oxaliplatin or carboplatin.

[0067] In another embodiment of the invention, the COMBINATION OF THEINVENTION comprises a vasculostatic of formula II

[0068] wherein r is 0 to 2, n is 0 to 2, m is 0 to 4,

[0069] R₁ and R₂ (i) are lower alkyl or

[0070] (ii) together form a bridge in subformula II*

[0071] the binding being achieved via the two terminal carbon atoms, or

[0072] (iii) together form a bridge in subformula II**

[0073]  wherein one or two of the ring members T₁, T₂, T₃ and T₄ arenitrogen, and the others are in each case CH, and the binding isachieved via T₁ and T₄;

[0074] A, B, D, and E are, independently of one another, N or CH, withthe stipulation that not more than 2 of these radicals are N;

[0075] G is lower alkylene, lower alkylene substituted by acyloxy orhydroxy, —CH₂—O—, —CH₂—S—, —CH₂—NH—, oxa (—O—), thia (—S—), or imino(—NH—);

[0076] Q is lower alkyl;

[0077] R is H or lower alkyl;

[0078] X is imino, oxa, or thia;

[0079] Y is unsubstituted or substituted aryl, pyridyl, or unsubstitutedor substituted cycloalkyl; and

[0080] Z is amino, mono- or disubstituted amino, halogen, alkyl,substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro,cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- orN,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo,phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl,phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z beingthe same or different from one another if more than 1 radical Z ispresent;

[0081] and wherein the bonds characterized, if present, by a wavy lineare either single or double bonds;

[0082] or an N-oxide of the defined compound, wherein 1 or more N atomscarry an oxygen atom, or the salt of such compound having at least onesalt-forming group. Preferably, the compound of formula II to beemployed is PTK787.

[0083] The terms used for the definition of the compound of formula IIhave the meanings as defined in WO98/35958, which definitions are hereinincluded by reference.

[0084] In the compound of formula I preferably A represents O. R islower alkyl, e.g. ethyl or, most preferably, methyl. Z is preferably O.

[0085] The COMBINATION OF THE INVENTION can be a combined preparation ora pharmaceutical composition.

[0086] Moreover, the present invention relates to a method of treating awarm-blooded animal having a proliferative disease, in particularprostate cancer, especially hormone refractory prostate cancer with bonemetastasis, comprising administering to the animal a COMBINATION OF THEINVENTION in a quantity which is jointly therapeutically effectiveagainst a proliferative disease and in which the combination partnerscan also be present in the form of their pharmaceutically acceptablesalts.

[0087] Furthermore, the present invention pertains to the use of aCOMBINATION OF THE INVENTION for the delay of progression or treatmentof a proliferative disease and for the preparation of a medicament forthe delay of progression or treatment of a proliferative disease.

[0088] Additionally, the present invention pertains to the use of a abisphosphonate, a platinum compound or a vasculostatic compound incombination with an epothilone derivative of formula I in which compoundA represents O or NR_(N), wherein R_(N) is hydrogen or lower alkyl, R ishydrogen or lower alkyl, and Z is O or a bond, for the preparation of amedicament for the delay of progression or treatment of a proliferativedisease.

[0089] Moreover, the present invention provides a commercial packagecomprising as active ingredients COMBINATION OF THE INVENTION, togetherwith instructions for simultaneous, separate or sequential use thereofin the delay of progression or treatment of a proliferative disease.

[0090] The following Examples illustrate the invention described above;they are not, however, intended to limit the scope of the invention inany way. The beneficial effects of the COMBINATION OF THE INVENTION canalso be determined by other test models known as such to the personskilled in the pertinent art.

EXAMPLE 1 PC-3MM2 Human Prostate Carcinoma Cells Grown Intratibia inNude Mice

[0091] A cell suspension (2×10⁵ cells) of the human prostate carcinomaline PC-3MM2 is injected into the tibia of nude mice. The growth of thetumor in this model leads to bone destruction that is clearly visibleafter 4 weeks. Treatment with the compounds is started 7 days afterinjection of the tumor cells. At this time animals are sorted intogroups with equivalent mean and range of tumor sizes. Treatment is thenrandomized to the different groups and treated with vehicles only; with(a) a bisphosphonate, e.g. zoledronic acid; a combination partner (b),e.g. epothilone B; or the combined partners (a) and (b), e.g. zoledronicacid and epothilone B. Analysis after 3-4 weeks of treatment includesestimation of bone destruction and tumor load.

EXAMPLE 2 Bisphosphonate and an Epothilone in DU145 Human ProstateCarcinoma Tumor Fragments Grown s.c. in Nude Mice

[0092] DU145 human prostate carcinoma tumors are grown s.c. in nudemice. Tumor fragments (approximately 25 mg each) are implantedsubcutaneously (s.c.) into the left flank of nude mice. Treatment withthe compounds is started when tumors reach a size of 80-100 mm² (usuallyafter 10-15 days). At this time animals are sorted into groups withequivalent mean and range of tumor sizes. Treatment is then randomizedto the different groups and treated with vehicles only; with (a) abisphosphonate e.g. zoledronic acid; a combination partner (b), e.g.epothilone B; or the combined partners (a) and (b), e.g. zoledronic acidand epothilone B. Tumor size (measured with calipers) and body weightare assessed every 3-5 days.

EXAMPLE 3 Oxaliplatin and Epothilone B in DU145 Human Prostate CarcinomaTumor Fragments Grown s.c. in Nude Mice

[0093] DU145 human prostate carcinoma tumors are grown s.c. in nudemice. Tumor fragments (approximately 25 mg each) are implantedsubcutaneously (s.c.) into the left flank of nude mice. Treatment withthe compounds is started when tumors reach a size of 80-100 mm² (usuallyafter 10-15 days). At this time animals are sorted into groups withequivalent mean and range of tumor sizes. Treatment is then randomizedto the different groups and treated with vehicles only; with (a)oxaliplatin; (b) epothilone B; or the combined partners (a) and (b),administred either simultaneously or sequentially in any order. Tumorsize (measured with calipers) and body weight are assessed every 3-5days.

EXAMPLE 4 Carboplatin and Epothilone B in NCI-H596 Human Lung CancerTumor Fragments Grown s.c. in Nude Mice

[0094] In the same model as used in Example 3, but employing the lungtumor cell line NCI-H596, the superior efficacy of the combinationconsisting of carboplatin and epothilone B compared to the single drugscan be demonstrated.

EXAMPLE 5 PTK787 and Epothilone B in DU145 Human Prostate CarcinomaSubcutaneous Xenografts in Nude Mice

[0095] DU145 human prostate carcinoma cells are grown s.c. in nude mice.Tumor cell (10⁶) are injected subcutaneously (s.c.) into the left andright flanks of nude mice. Treatment with the compounds is started after25-32 days when tumors reach a size of 80-100 mm². At this time animalsare sorted into groups with equivalent mean and range of tumor sizes.Treatment is then randomized to the different groups and treated withvehicles only; with 2 mg/kg epothilone B given once a weekintravenously; 50 mg/kg PTK787 administered once a day p.o.; or thecombined partners epothilone B and PTK787. Tumor size and body weightchanges are measured with calipers on a weekly basis. The results showadditive tumor growth inhibition without concomitant increased bodyweight loss.

EXAMPLE 6 Epothilone B and PTK787 in B16 Syngeneic Mouse MelanomaSubcutaneous Xenografts in Black Mice

[0096] B16 mouse melanoma cells (5×10⁴) are injected subcutaneously(s.c.) into the ears of black mice. Treatment with the compounds isstarted after 7 days. At this time animals are sorted into groups withequivalent mean and range of tumor sizes. Treatment is then randomizedto the different groups and treated with vehicles only; with epothiloneB given once a week intravenously; with PTK787 administered once a dayp.o.; or the combined partners epothilone B and PTK787. Primary tumorgrowth is monitored on a weekly basis by computer-assisted analysis ofphotographic images of melanomas. Animals are necropsized 3 weeks aftertreatment initiation. Metastatic spread is assessed by weighing ofcervical lymph nodes.

1. A combination which comprises (a) a bisphosphonate, a platinumcompound or a vasculostatic compound and (b) an epothilone derivative offormula I

wherein A represents O or NR_(N), wherein R_(N) is hydrogen or loweralkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which theactive ingredients (a) and (b) are present in each case in free form orin the form of a pharmaceutically acceptable salt and optionally atleast one pharmaceutically acceptable carrier; for simultaneous,separate or sequential use.
 2. A combination according to claim 1 whichcomprises (a) carboplatin or oxaliplatin and (b) an epothilonederivative of formula I wherein A represents O or NR_(N), wherein R_(N)is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O ora bond, in which the active ingredients (a) and (b) are present in eachcase in free form or in the form of a pharmaceutically acceptable saltand optionally at least one pharmaceutically acceptable carrier; forsimultaneous, separate or sequential use.
 3. Combination according toclaim 1 wherein a bisphosphonate is employed selected from etridonicacid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid,ibandronic acid, risedronic acid and zoledronic acid.
 4. Combinationaccording to claim 3 wherein the bisphosphonate is zoledronic acid. 5.Combination according to claim 1 comprising a vasculostatic compound. 6.Combination according to claim 5 wherein the vasculostatic compound isPTK787.
 7. Combination according to claim 1 comprising an epothilonederivative of formula I wherein A represents O, R is lower alkyl orhydrogen and Z is O or a bond.
 8. Combination according to claim 1,which is a combined preparation or a pharmaceutical composition. 9.Method of treating a warm-blooded animal having a proliferative diseasecomprising administering to the animal a combination according to anyclaim 1 in a quantity which is jointly therapeutically effective againsta proliferative disease and in which the compounds can also be presentin the form of their pharmaceutically acceptable salts.
 10. Method oftreating according to claim 9 wherein a bisphosphonate is employed andthe proliferative disease is hormone refractory prostate cancer withbone metastasis.
 11. Method of treating according to claim 9 whereincarboplatin or oxaliplatin is employed and the proliferative disease isovarian cancer, lung cancer, head or neck cancer, cervix cancer,prostate cancer or colon cancer.
 12. Method of treating according toclaim 9 wherein PTK787 is employed and the proliferative disease isovarian cancer, lung cancer, head or neck cancer, cervix cancer,prostate cancer or colon cancer.
 13. A pharmaceutical compositioncomprising a quantity which is jointly therapeutically effective againsta proliferative disease of a pharmaceutical combination according toclaim 1 and at least one pharmaceutically acceptable carrier.
 14. Acombination according to claim 1 for use in the delay of progression ortreatment of a proliferative disease.
 15. Use of a combination accordingto claim 1 for the preparation of a medicament for the delay ofprogression or treatment of a proliferative disease.
 16. Use of abisphosphonate in combination with an epothilone derivative of formula I

in which compound A represents O or NR_(N), wherein R_(N) is hydrogen orlower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, for thepreparation of a medicament for the delay of progression or treatment ofa proliferative disease.
 17. Use of cisplatin, carboplatin oroxaliplatin in combination with an epothilone derivative of formula I

in which compound A represents O or NR_(N), wherein R_(N) is hydrogen orlower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, for thepreparation of a medicament for the delay of progression or treatment ofa proliferative disease.
 18. Use of a vasculostatic compound incombination with an epothilone derivative of formula I

in which compound A represents O or NR_(N), wherein R_(N) is hydrogen orlower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, for thepreparation of a medicament for the delay of progression or treatment ofa disease associated with deregulated angiogenesis.
 19. Use according toclaim 18, wherein the vasculostatic compound is PTK787.
 20. A commercialpackage comprising (a) a bisphosphonate, a platinum compound or avasculostatic compound and (b) an epothilone derivative of formula I

wherein A represents O or NR_(N), wherein R_(N) is hydrogen or loweralkyl, R is hydrogen or lower alkyl, and Z is O or a bond, together withinstructions for simultaneous, separate or sequential use thereof in thedelay of progression or treatment of a proliferative disease.